Frank Hone and Rob Benson are executive vice-presidents in the Global Business Group at Healthworld Communications Group. Hone can be reached in New York at frank.hone@healthworld.com. Benson can be reached in London at rob.benson@healthworld.co.uk.

In 1996, Sandoz (now Novartis) decided to brave new waters to create consumer demand for the antifungal Lamisil (terbinafine) in the United Kingdom. But with European law forbidding pharma companies to conduct brand-name advertising, Sandoz needed to find another way to encourage patients to talk with their doctors about onychomycosis and its treatment options. So the company re-named the condition the more consumer-friendly "fungal infection" and took out newspaper ads asking readers to call or write to "Step Wise" for a free brochure on foot care. 	

By creating a consumer-relevant name for their patient education program, Sandoz branded the solution, without naming the prescription product in the ad. They also effectively articulated the unmet needs of many people and created a way for sufferers to make an informed choice and take action. This first foray into direct-to-consumer (DTC) advertising in Europe drew protests from some physician groups who filed legal protests claiming the campaign would improperly influence prescribing. But the courts overruled the protests, paving the way for other pharma marketers to reach out to consumers.	

And they did. Despite the perception that DTC is illegal in Europe, pharma companies have been conducting—and refining—consumer-targeted campaigns since the Sandoz test case. Although many US marketers believe that those European initiatives are DTC's poor stepchild, European legal restrictions on brand-name promotion have, in effect, encouraged a significant level of integrated marketing. The net result is an approach to marketing that addresses attitude and behavior change in addition to awareness building. While DTC focuses mainly on advertising to mass audiences to drive new prescriptions, the European initiatives take a more strategic approach by targeting patients who are likely to use the medication. The approach lends itself to tactics—executed in collaboration with healthcare professionals and with the support of other influencers—that build brand loyalty and improve compliance because they help patients gain a deeper understanding of the disease and therapeutic options.	

This article discusses the emergence of patient mobilization strategies in Europe and explains how to develop and deploy them. It also illustrates how US and European marketing platforms—which aren't as radically different as they may seem—are actually converging.	

In Europe, regulations stipulate that companies can disseminate only unbranded information in their promotional initiatives to consumers. The European Council Directive 92/28/EEC "prohibits the advertising to the general public of medicinal products which are on medical prescription only." However, "statements relating to human health or diseases, provided there is no reference, even indirectly, to medicinal products" are permitted. In other words, disease education is allowed. Also, the European Union marketplace, as it relates to healthcare, is far more conservative. European patients are less accepting of in-your-face branded ads than the US audience, and European physicians feel more strongly than US physicians about their traditional role as the gatekeepers of health information and prescribing decision makers. So companies realize that an effective way to reach commercial goals is to cultivate long-term patients through education, rather than acquiring new consumers through brand-awareness advertising. 	

Patient mobilization strategies rely heavily on public relations and a wide range of marketing communications vehicles to build an environment favorable to a brand's prescribing and long-term usage. European marketers' approach is subtler than DTC and ensures that patient groups and other stakeholders buy into, and participate in, the dissemination of patient education and disease information. Patient mobilization also depends on the effective delivery of messages and favors vehicles that closely target the intended audience—such as brochures, booklets, advertorials, and testimonials, in addition to targeted advertising—and the Internet. That contrasts with DTC, which primarily uses television advertising aimed at a broad consumer audience.	

Bladder banter: Pharmacia (now Pfizer) launched a patient mobilization campaign on behalf of its incontinence treatment Detrusitol. Magazine advertising included a quiz that patients could take to determine whether they should speak with their doctors. Other elements included a phone number patients could call to receive information about bladder problems specifically tailored to their needs.		

An example of patient mobilization in action is the disease awareness campaign mounted by Pharmacia (now Pfizer) on behalf of its incontinence treatment Detrusitol (tolterodine) in the UK. Working closely with groups such as the Royal College of Nursing and the Patients Association, Pharmacia rolled out an educational advertising campaign called "Greater Freedom from Bladder Problems." The campaign aimed to break down the stigma of incontinence, partly by replacing the medical term "incontinence" with the more consumer-friendly phrase "bladder problems." It included a symptom quiz that patients could take to determine whether they should speak with their doctors. It also featured direct-response elements, such as a phone number patients could call to receive an information booklet tailored to their needs. Pharmacia also informed all general practitioners of the campaign by mail and held a series of accredited workshops for physicians.	

That orchestrated approach, first communicating with physicians and then with patients, is a trademark of patient mobilization. Because European marketers can't direct consumers to talk to their doctors about a specific product, marketers must coordinate their branded communications to health professionals and unbranded disease information to consumers to build an "ownable" point of view about the disease that leads to a discussion of the promoted brand's benefits. 	

Patient mobilization also relies heavily on public relations to get the buzz out to consumers. Typically, health news raises disease awareness, but it can sometimes even introduce consumers to a brand.	

The power of PR varies, depending on editorial interest. For example, the media largely shaped end-user interest and ultimate demand for erectile dysfunction products. In France, the most conservative of European markets, journalists began referring to Lilly's Cialis (tadalafil), which has a 36-hour therapeutic action, as "Le Weekend." The term, now part of the vernacular, can be used by the brand owner as a surrogate branded communicational vehicle working essentially within the letter of the law.	

Patient mobilization has an advantage over DTC because the promotion extends well beyond the promotional peaks of launch, ensuring a continuity of brand performance and building an enduring relationship with customers, instead of focusing on the return of a single media investment.		

Stabilizing sales: Roche created ads such as this one that ran in women's magazines in Germany, which more closely targeted patients and promoted persistency and compliance programs.; French connection: In 2002, Sanofi-SynthÃÂ©labo distributed this poster in France to increase awareness of several neurological diseases in support of its products Solian, Stilnox, and Tranxene.	

The story of Xenical (orlistat) illustrates this. Roche spent heavily on its US DTC launch campaign, which focused on creating demand through branded TV commercials. However, the campaign didn't effectively convey to US consumers the need for lifestyle modification along with the therapy. It also had difficulty articulating the drug's potential side effects—including the excretion of unabsorbed fats—in a consumer-friendly way. Although the company was successful in achieving new patient starts, low rates of persistence and compliance hurt overall sales. 	

Roche decided to launch its consumer campaign in Europe based on lessons learned in the United States. The company worked with healthcare professionals to establish self-help and support programs for patients and launched a series of ad campaigns across Europe. This time, it more rigorously defined and targeted prospective patients. Telephone help lines offered consultations and advice from qualified nurses. The nurses weren't there to encourage patients to ask their doctor for the product; rather, they screened callers to ensure that only appropriate patients were asking physicians for information about prescription diet therapies. Those help lines also captured callers' data, which were used, with permission, for future support programs. 	

Published case studies in key European markets have since indicated that not only did this more considered and concentrated marketing approach help stabilize brand sales volatility, but its focus on encouraging longer-term use and appropriate diet and lifestyle adjustment created a new level of physician confidence in the role the brand could play in addressing weight-related disorders.	

The campaigns for Pfizer's Viagra (sildenafil) and Lilly's Cialis show that patient mobilization takes a complete view of the promotional mix and fosters patients' long-term relationships with brands. There are three basic building blocks to patient mobilization campaigns:	

 This phase sets the stage for brand launch. In its market preparation, Pfizer created the term "erectile dysfunction," which helped condition the emerging market for Viagra by de-stigmatizing male impotence and establishing a need for treatment. The company worked with the Impotence Association and the Men's Health Forum to foster discussions about the disease and set the stage for the brand with discussion aids such as a list of questions for patients to ask their doctors.	

Similarly, Lilly created its own association called ManMatters before it launched Cialis in Europe. Lilly built on Pfizer's market-conditioning activities by segmenting the audience, targeting those for whom Viagra wasn't fully effective and those who still had unmet expectations and a propensity to take further action. This approach illustrates the value of using segmentation based on both demographics and psychographics to more closely align a brand's performance benefits with its most appropriate (and potentially most loyal and profitable) users. 	

In effect, Lilly sought to mobilize an unmet aspirational need by focusing its campaigns less on the medical problem of erectile dysfunction and more on the emotional dimension of sexual relationships. The company carved out that aspect, so that even when patients viewed unbranded information, they knew it wasn't Viagra, but rather something new, prompting associative beliefs that it was potentially better and worth checking out with their physicians.	

Both Pfizer and Lilly used campaign branding to tie in patient education with the sales force efforts and targeted physicians with complimentary messages. This wasn't organized just to link all communication around the brand name, it also provided a necessary educational vehicle to inform, guide, and motivate physicians themselves to recognize and address both the medical condition and patient needs within the context of modern primary care.	

During the launch phase, consumer communications encourage patients to have productive dialogues with their physicians. Pfizer, like many other companies in Europe, now places a heavy focus on implementing customer relationship management (CRM) programs within this phase of patient mobilization campaigns, in part so it can obtain patient information to enable post-prescribing communications.	

Pfizer built CRM into its national media campaign, using coupons consumers could mail in to receive information packets about erectile dysfunction. Pfizer responded to consumers with follow-up questionnaires, which not only created an information platform reinforcing the value and benefits of the brand, but also assisted the company in refining future communication and content.	

In another campaign, Pfizer built up its brand-related imagery and value associations by using the soccer legend Pele a front man for its 2002 campaign for erectile dysfunction. By using a well-respected athlete with the problem, it helped consumers overcome the myth that erectile dysfunction doesn't happen to macho guys. 	

In its promotion, Lilly used print advertising with a variety of direct-response mechanisms such as patient help lines, direct-response booklets, and dedicated website support. The company focused on generating a new level of patient physician discussion based on informed choice and picking the right therapy for the patient. The campaign featured materials with headlines such as "Why Treating Erection Problems Is All About Choice" and introduced personal-style testimonials such as: "The first treatment I tried wasn't right for me. However, after going back to see my doctor and talking further about all the options available, we did find a treatment that was right for me. My life has been completely transformed." Thus, even in unbranded situations, Lilly was able to drive competitive differentiation. Cialis now controls 20-30 percent of the European erectile dysfunction market.	

PelÃÂ© speaks to patients: Pfizer has used patient mobilization to drive consumer demand for Viagra. Pfizer built up its brand-related imagery and value associations by using the soccer legend PelÃÂ© as a front man for its 2002 campaign for erectile dysfunction. By using a well-respected athlete with the problem, it helped consumers overcome the myth that erectile dysfunction doesn't happen to macho guys.	

 This third phase is the most important commercially because patient compliance and loyalty determine long-term brand profitability after launch. Many brand managers now recognize this. For example, in the UK, Pfizer is currently using the "voice" of the third-party Men's Health Forum to run targeted radio ads that encourage men to talk about erectile dysfunction with their doctors. This message is backed by facts on the number of men who have already taken the first step toward treatment assistance and a "better love life." The ads help reinforce the confidence and loyalty of existing patients while adding further endorsement to encourage potential new Viagra users to step forward and see their physician.	

Other programs, such as Lilly's ManMatters, offer a range of web-based pre- and post-prescribing services and information content that includes not just advice on erectile dysfunction but detailed insight into specific treatment options, as well as access to patient case studies and relationship guidance advice.	

Companies are increasingly using physician-supplied patient starter packs containing user leaflets, tips, FAQ advice, and patient diaries at the initial prescribing consultation to help ensure the right patient/brand compliance from the start. Those packs create the basis of initial patient expectations with resulting patient treatment outcomes fostering repeat brand loyalty in terms of prescribing decision making and user preference.		

Less is more: Recently, Pfizer introduced ChoLESSterol,a consumer initiative that aims to create a call to action about cholesterol control and heart health. The company launched the campaign in support of Lipitor's market-leading position in cardiovascular, the planned launch of Caduet, and the likelihood that Europe will switch statins over the counter in the near future.	

In 2003, Pfizer launched another multiplatform consumer initiative that further illustrated the enduring relevance and logic behind the three patient mobilization building blocks. Taking a wider category position, Pfizer introduced "ChoLESSterol," a campaign that used targeted press advertising and public relations to create a consumer call to action about cholesterol control and heart health. Various copy treatments targeted "at risk" groups such as diabetic patients and those who had suffered a heart attack in the past.	

Pfizer used follow-through direct-marketing programs and "opt-in" CRM activities endorsed by patient groups to deepen and develop patient interest, understanding, and involvement.	

Pfizer's commercial rationale for the campaign rests on its strength in the cardiovascular category with Lipitor (atorvastatin), the planned launch of Caduet (amlodipine besylate/atorvastatin calcium), as well as the untapped business potential of major undertreatment in that area. Alongside such growth ambition, it was also a smart pre-emptive and protective initiative, as the likelihood of statins switching to over the counter in European markets moves closer toward reality in 2004 and 2005.		

As the European market develops patient mobilization campaigns, US-style DTC has also significantly evolved. The days of explosive DTC spending that began in 1997 with FDA's relaxation of broadcast regulations have become more cautious. Marketers are feeling the pressure against aggressive DTC campaigns from critics as well as cost-cutting managers, and have slowed their DTC spend.	

Brands like Claritin (loratadine) and Prilosec (omeprazole) that once defined the era of massive DTC campaigns are now OTCs, while marketers working on others like Propecia (finasteride), Meridia (sibutramine), and Xenical have shifted their media schedule away from television advertising because of the difficulty in effectively communicating a positive brand message in the face of extensive or difficult fair balance.	

Even for the most successful brands, there are real questions as to whether DTC is worth it. Recently, the US Congress proposed restrictions against DTC; several state legislatures took up bills; large employers focused on generics—like General Motors with its Generics First campaign to workers and retirees; and managed-care plans have stepped up their reimbursement penalties on advertised brands with tiered co-pays.		

Although the evolution toward an era of less television advertising and more cautious marketing won't rapidly transform the US DTC market, it may create an advertising paradigm more similar to the European system. The United States will always be more aggressive in execution, but marketers that recognize that the quality of communication and depth of patients' relationship with a brand may solve one significant problem in their marketing plan—the lack of patient persistence on chronic therapies.	

Some US companies have started to address the problem by replacing aggressive branded awareness messages on television with more targeted and education-based campaigns. For example, Pfizer is spending money on promoting its glaucoma disease awareness site instead of its product site supporting Xalatan (latanoprost). And it makes sense: After all, the more patients understand their condition and the relevance of their medical treatment to managing their health, the stronger their adherence is. That opportunity should be incentive enough for marketers to shift their priority from scooping up new patients to building brand loyalty and advocacy to retain existing customers.	

New FDA guidelines will also encourage US marketers to take steps along that path. In time, many companies will replace promotional messages with educational content.	

Marketers who are shifting their perspective are placing a new emphasis on long-form television documercials, video on demand, targeted print advertising, interactive online campaigns, in-office communications, relevant sponsorships, and appropriate direct-marketing approaches. Abbott, for example, is using an unbranded disease education campaign to communicate with US consumers about rheumatoid arthritis. Much of the campaign's focus can be found on the website www.controlRA.com, which offers consumers targeted information. It also offers an unbranded reply card in its advertising that allows users to receive free information about new treatment options—a big departure from competitors such as Celebrex (celecoxib) and Vioxx (rofecoxib).	

With Internet growth, globalization, and the rise of patient empowerment, a phenomenon may soon take shape: US DTC advertising may start to mellow at the same time that pharma marketers are stepping up their efforts to drive the most appropriate consumer demand in European markets.	

As a result, in Europe, as in the United States, patient mobilization can be seen in new brand launches, category management initiatives, and life-cycle planning processes, particularly among the world's top 15 pharma companies who have launched campaigns in Europe and who can now increasingly share best practices within their international affiliates.	

Articles

Features

In 1996, Sandoz (now Novartis) decided to brave new waters to create consumer demand for the antifungal Lamisil (terbinafine) in the United Kingdom. But with European law forbidding pharma companies to conduct brand-name advertising, Sandoz needed to find another way to encourage patients to talk with their doctors about onychomycosis and its treatment options. So the company re-named the condition the more consumer-friendly "fungal infection" and took out newspaper ads asking readers to call or write to "Step Wise" for a free brochure on foot care.

DTC: European Style

Wayne M. Dankner, MD, is a senior medical director of North American Medical Services, and Hua DuprÃ©, MD, PhD, is a director of project management and operations, for Parexel International.

For a patient who is running out of hope, waiting for a drug to be approved can be interminable. Even on the fast track, a review can take six months or longer. Some patients with life-threatening diseases cannot afford to wait. In response, many countries have developed expanded access programs (EAPs) that give patients with no other viable alternative access to medically important drugs before they are commercialized.	

The benefit of expanded access is clear. In fact, much of the groundwork for FDA's current policy regarding EAPs was driven by the AIDS community and its vocal demand for access to experimental treatments in the 1980s and early 1990s. Regulatory agencies such as FDA also stand to gain, because an EAP can generate additional safety data on the new product. But what about pharmaceutical companies? What is the benefit to them?	

This article outlines the benefits of EAPs, describes how programs are structured in the United States and abroad, examines several regulatory issues associated with EAPs, and highlights the management and logistical issues that should be taken into account when considering implementing them.	

For pharmaceutical companies, EAPs create several advantages, including:	

expanded safety data across a more clinically and ethnically diverse population than often encountered in clinical trials

opportunity for larger groups of physicians to gain experience with both the benefits and adverse events associated with the drug

pre-approval exposure to hundreds or thousands of practicing physicians

the potential to develop valuable clinical experience that may support additional labeling and/or product-related publications and communications.

Those benefits—and in some countries, the possibility of generating revenue—can make it well worth a sponsor's while to consider EAPs for certain products.

Making the drug available on a global scale can multiply those benefits across a wider marketplace, but the process can be challenging because of differences in regulations and philosophy from one country to the next, particularly in Europe. A thorough understanding of those variations can facilitate a successful global EAP. Such insight is especially important given that the programs are conducted under regulatory review.	

EAPs—sometimes called compassionate use programs—have been most commonly used in oncology and HIV/AIDS, although their application is expanding into such areas as neuropathy, hepatitis B, sepsis, and coagulopathy (a disease affecting blood coagulation).	

Pharmaceutical companies should consider EAPs when they are developing a new product for a life-threatening illness or disorder that leads to major disability and when there are patients who have exhausted alternative therapies in that particular therapeutic category. However, the decision must be weighed carefully. Regulatory agencies are particularly sensitive to demonstration of patient need. Programs that the agencies perceive to have marketing value only will not be approved.	

EAPs are usually established during Phase III of development, between pivotal trials for approval and receipt of marketing authorization. At that point, the sponsor has accumulated sufficient safety and efficacy information to permit use of the new drug in a minimally controlled outpatient setting.	

Patient entry criteria for EAPs need not be as strict as they are for clinical trials but should match the indications in the proposed drug label. Patients who participate in an EAP often have not been eligible for a Phase III trial because of co-morbidity, disease stage, or concomitant medication use—or simply because they reside in countries where no clinical trial is available. In the United States, where EAPs are administered primarily through an FDA–designated Treatment Investigational New Drug (IND), a clinician must still determine patient eligibility, but the inclusion/exclusion criteria are more open.	

In certain countries, particularly the United States, an EAP is similar to a standard Phase IIIb trial: both are conducted according to a specific protocol and require Institutional Review Board (IRB) oversight and informed consent from patients. The major difference between an EAP and a standard Phase IIIb clinical trial is that no efficacy data are collected. Data collection for an EAP is usually limited to demographic and safety information and involves far fewer case report forms (CRFs). Data monitoring can be done remotely instead of performing on-site visits for source data verification.	

In other countries, EAPs can be administered through open-label Phase III trials, cohort patient programs, or named-patient programs. In those capacities, it is the pharmaceutical company's primary role to supply the drug, and it is the physician's responsibility (and decision) to enroll patients.	

Unlike a standard clinical trial, an EAP involves an unknown number of patients and sites—which can make it a challenge to plan for adequate production of drug supply, especially before the product has been fully commercialized. Inadequate supply in the face of high demand could adversely affect the good will the company hopes to generate.	

Another potentially significant area of difference is medication cost. In Phase III trials, the sponsor provides the medication. In certain types of EAPs, in countries such as France or the United Kingdom (but not typically in the United States), the treatment cost may be covered by a national or private insurance system, and the manufacturer has the option to charge a fee for the drug. Charging payers for the product enables the company to recover some manufacturing, research, development, and handling costs, particularly in the case of new biotechnology products.	

In the United States, FDA has allowed expanded access to new products since the late 1980s. Current US regulations provide for three types of EAPs:	

Emergency Use IND in life-threatening situations before approval by an IRB (most often applied for by the treating physician)

Compassionate Use IND requested by a practitioner to provide access for a single patient under an existing or new protocol

Treatment IND protocol added to an existing IND application by the pharma sponsor to cover an unspecified number of patients to be treated by physicians who follow the protocol.

The Treatment IND offers the greatest opportunity for companies and regulatory agencies to collect data, but the route has potential pitfalls, most notably, the chance that a serious adverse event which may not be related to the drug itself could jeopardize approval.

Most pharma sponsors and US contract research organizations are accustomed to FDA guidelines. Outside the United States, the options become a little more complex. In European Union member states, Council Directive 65/65/EEC (later amended by 89/341/EEC) governs the compassionate use of medicinal products and allows EU member states to make unapproved innovative drugs available to patients outside of clinical trials.	

Two main types of programs may be used in Europe, depending on the applicable national regulations:	

Compassionate use on a named-patient basis, involving individual patients. Although in most cases, these programs are set up by the pharma sponsor, the request of using the new drug is from the treating physician on an individual patient basis, and the sponsor functions primarily to ensure drug distribution.

Compassionate use involving a large number of patients (cohort program).

In certain countries such as France, pharma sponsors can apply for a temporary authorization that needs to be renewed every year. The procedure does not require a physician prescription. All patients who meet the criteria can receive the treatment, and the cost is covered by the insurance system.

Denmark, Finland, France, Greece, Luxembourg, the Netherlands, Sweden, and the United Kingdom all have programs both for a cohort of patients and for individual named patients. Other European countries have only named-patient programs. In many, expanded access for a larger group of patients requires a Phase IIIb clinical trial or safety study—a more complex and time-consuming route than a Treatment IND.	

In determining the geopolitical scope of an EAP, pharma companies must balance the potential costs with the potential benefits of exposure, good will, and enhanced data. Differences in regulations and medical practice from one country to the next will affect each of those factors. Ultimately, where the EAPs will be offered is a decision that companies must make based on disease prevalence and future market availability of the drug in that country.	

All regulatory agencies require some type of safety reporting for EAPs. A cohort-basis program usually gives the sponsor the greatest degree of control over the program's conduct and provides access to safety data collected by participant physicians. Under most countries' named-patient programs, the pharma company will not receive safety data directly from the treating physician. In the United Kingdom, physicians report adverse events (AEs) to the Medicines Control Agency (MCA), but the sponsor may not learn of them for several months, possibly even a year, therefore missing the opportunity to gather more information when an event occurs.	

In other countries, including Germany, however, a Phase IIIb approach may often be preferable to a named-patient program because of conflicting ethical and legal issues that affect compassionate use of non-approved drugs. Such conflicts, on the one hand, can lead to advocacy for access of non-approved drugs for those who would benefit most, but at the same time, they can increase the potential liability for sponsors and individual physicians for providing non-approved medications.	

Thus, strict adherence to international guidelines such as the Declaration of Helsinki, International Conference on Harmonization (ICH), and Good Clinical Practice (GCP) are critical for named-patient programs. Yet because those same guidelines are in effect for Phase IIIb studies, sponsors may gain more control over the conduct of the study through the Phase IIIb approach. However, companies must weigh the advantages gained through greater control—such as improved screening of eligible patients and better collection of patient demographic and safety data—against the cost of more restrictive entry criteria, which requires heavy administrative and logistic supports.	

Cost recovery is another strategic issue that companies must consider when determining what type of EAPS to pursue and in which countries. If a company decides to charge for the product to offset the cost of the EAP, that price remains the reference point for further price negotiations with regulatory bodies and health insurance systems when the drug goes to market. In all cases, an experienced contract service provider can help sponsors make cost/benefit decisions and, in turn, execute a successful EAP.	

Generally, EAPs involve physicians who may not be experienced clinical researchers and are not monitored by on-site clinical research associates (CRAs). In light of those realities, sponsors must carefully design case report form data collection procedures to ensure complete, accurate, and timely safety reporting.	

For Treatment INDs and named-patient or cohort programs, a centralized coordination center usually is the most efficient, cost-effective approach to EAP management. Global EAP programs usually require centralized coordination both in the United States and in Europe to cover all of the appropriate time zones. A coordination center in Asia may be added if the program covers that area, too. Since EAPs involve physicians who may use the local language, sponsors may want to consider staffing centers with multilingual personnel.	

A properly staffed center can perform clinical monitoring and document management—functions that otherwise would be carried out by CRAs or at the home office. The staff can also screen, enroll, and initiate sites; help physicians gain access to the program; and review inclusion and exemption requests. The coordination center can function as a facility for drug distribution and re-supply, as well as for safety reporting and safety event management. The center can also collect CRFs and collate regulatory documents, essentially acting as the central conduit for all critical information that needs to be transmitted into the sponsor's larger database. (See "EAP Process Flow," page 67.)	

Collecting EAP data can be challenging. Although US physicians must sign Form 1572 recognizing their regulatory obligations, they are not compensated for their efforts, as is true in most countries. So it is not unusual to receive incomplete CRFs. A simple, well-designed CRF and a monitoring/follow-up process can help increase the likelihood that physicians will provide complete information. Still, an experienced central center staff is necessary to provide all-important query follow-up, as the coordination center is often the sponsor's only link with physicians.	

Because participant sites may not be familiar with terminology, completion of AE forms often requires multiple queries to ensure that the appropriate information is collected. Coordination center staff should be trained to conduct appropriate safety follow-up and refer all AEs to the sponsor's designated safety group.	

Finally, a coordination center can support the pharmaceutical company's communication strategy by providing a harmonized voice and a consistent message to both physician and patient communities. At the same time that it must seek uniformity, a global EAP center must have the experience, knowledge, and flexibility to understand local variability within the program and work within the boundaries of local regulations.	

For a patient who is running out of hope, waiting for a drug to be approved can be interminable. Even on the fast track, a review can take six months or longer. Some patients with life-threatening diseases cannot afford to wait. In response, many countries have developed expanded access programs (EAPs) that give patients with no other viable alternative access to medically important drugs before they are commercialized.

The Ins and Outs of EAPs

Michael D. Lam is Pharmaceutical Executive's Associate Editor. 

Pfizer is embroiled in a whistleblower lawsuit based on an unproven legal theory with the potential "to scare the hell out of a lot of drug companies," says attorney Alan Minsk of Arnall Golden Gregory. If upheld, even those compliant with FDA regulations for off-label promotion might still be liable for Medicaid fraud under the federal False Claims Act (FCA). 	

 (a unit of Warner-Lambert, acquired by Pfizer, liabilities and all, four years ago), could be enormous. Violators of FCA are excluded from government business and pay triple damages and civil penalties between $5,000 and $11,000 for each false claim-all of which likely motivated Pfizer to set aside more than $400 million recently, presumably to settle the matter.	

What does this suit mean for pharma? US Attorney James Sheehan, a veteran healthcare fraud investigator, sees the suit as a "green light" for whistleblowers, the first of many to come. To James Moorman, executive director of Taxpayers Against Fraud, an organization that supports whistleblowers and their attorneys, it's an "outlier," one of a kind. 	

Who's right? What's at stake? And what can pharma do?	

Like the flu, off-label promotion problems seem to afflict the industry in a new form every year. The Parke-Davis bug is not only the latest strain, but in certain respects the most unlikely. The plaintiff, David Franklin, PhD, a microbiologist employed by Parke-Davis as a medical liaison for five months in 1996, filed a lawsuit that year alleging that the company had engaged in unlawful activities, including kickbacks and sham research, to promote off-label use of Neurontin (gabapentin), an anti-convulsant approved for the treatment of epilepsy. 	

 echoes previous actions against pharma firms. (See "Whistleblower Fraud Cases.") But Franklin's suit contains a troubling new legal theory that to date has withstood the court's scrutiny. It has two parts. The first, Minsk says, is the contention that, although Parke-Davis never directly submitted a Medicaid claim the company "in effect caused the false claim to be made." 	

In a motion to dismiss the suit, the company argued, as Minsk put it, "Wait a second, we don't submit the paperwork. That's the doctors and the pharmacies. Throw the claim out." But the court didn't.	

Why not? Because the allegation is not so outlandish after all. First, there's the basic legal principle, articulated by William Vodra, senior partner with Arnold & Porter, "that a company remains responsible for the foreseeable consequences of its activities." In particular, the FCA statute imposes liability on any person who "knowingly presents, or causes to be presented ... a false or fraudulent claim," with "knowingly" defined as actual knowledge, reckless disregard, or deliberate ignorance. It's easy to see that a company that promotes off-label use, however circumspectly, might reasonably foresee that a Medicaid claim would be submitted for that use.	

The second part concerns why the claims are fraudulent. Medicaid programs in most states cover the cost of off-label drug use (for which they are reimbursed by the federal government) as long as the unapproved indications are listed in any of three standard reference works (Drugdex, AHFS Drug Information, and US Pharmacopeia). However, eight states do not cover any off-label use under any circumstance. Because Medicaid reimbursement was sought for off-label use of Neurontin in these states, the claims were materially false. 	

 was a surprise for the industry," says a consultant who advises pharma on compliance issues. The connection between drug maker and the person who actually bills Medicaid is so attenuated, he says, "that this issue probably was not on the compliance radar screen of any pharmaceutical company." He likens it to "waking up one morning ... and wearing pants is suddenly viewed as inappropriate. If you're asked, 'Did you ever wear pants?' you have to say yes. But you never thought you were violating the law." 	

Minsk says, "The majority of drug companies promote off-label. If the court determines that a company can be held responsible for causing a false claim to be made, the US Attorney could shoot fish in a barrel if he or she wishes to go after almost any of them."	

 incentives to consider. "If Franklin walks out of this thing with $100 million," says Vodra, "I can certainly see people saying, 'This is something to get into.' Every single person in a marketing organization, from the bottommost sales rep up to the top levels of the company, might blow the whistle," he says. "Even the secretaries at headquarters can walk out, taking all the documents with them."	

 are just theoretical. And they are likely to stay that way. Every pharmaceutical company in a similar position has settled. So, the consultant says, "there's never been any proof that these theories really stand up." 	

 is settled, as seems likely, the trial court's rulings won't be reviewed by an appellate court, and will be "interesting opinions from one district court judge with no binding effect on any other," Vodra says. "That doesn't mean the court says it's a silly claim," says Minsk. "It doesn't mean the court says it's a victorious claim. It just simply means that somebody else is probably going to bring the issue up at another time."	

Why do companies uniformly settle FCA lawsuits? David Hyman, a professor at the University of Maryland school of law, says, "[Healthcare] providers who believe they are blameless are under tremendous pressure to settle, because of the legal expenses associated with mounting a defense and the high probability of bankruptcy and professional disgrace if the jury does not see things the same way."	

It is interesting to note that the costliest penalty is the seemingly paltry civil fine of $5,000–$11,000 per false claim. But, as Hyman points out, "because most healthcare providers typically submit a large number of modest claims, this structure means that statutory penalties generally dwarf actual damages, and quickly rise to staggering levels—as much as $1.1 million for every 100 false claims."	

What's more, companies "also run the risk of being excluded from federal programs and procurement," according to the compliance consultant, "which means not only that your products cannot be reimbursed by any federal program, but you may be excluded from all the other government contracts you have. That is a death sentence." As if that weren't enough, FCA cases need not be proved "beyond a reasonable doubt," the familiar standard in a criminal case. The plaintiff's charges must only be proved by a "preponderance of the evidence." No wonder that "prosecutors like the FCA," says attorney John Bentivoglio of Arnold & Porter, not just for its "broad scope of liability and expansive definition of knowledge," but also for its lesser burden of proof.		

Add it all up, the consultant says, and most companies decide a trial is not worth the risk. In Hyman's view, "The FCA makes it possible for the government and 

 relators to extract the healthcare equivalent of 'greenmail.'"	

Finally, the consultant says the government "always looks for a case that is easy to win or settle because they don't want to set any bad precedents." Moorman agrees: "This may not be the general perception, but the Justice Department is fairly conservative. They win over 95 percent of these False Claims Act cases. Does that strike you as risk taking?"	

 is unlikely to spawn many imitators. First, he says, "There's a rumor flying around that the Justice Department intends to extract a large amount of money from Pfizer in the form a huge criminal fine instead of False Claims Act damages, as part of a global settlement combining all civil and criminal liability in one shot. If they assign $300 million of that as a criminal fine and the rest as civil penalties, that means Franklin, whose share is based only on the civil penalty portion, gets less money, even though he did all the work." This, he believes, would discourage similar cases. "Most False Claims Act lawyers are going to say, 'This is a long tough slog.' If the US Attorney's office allocates all the money to criminal penalties? Talk about killing the incentive."	

Furthermore, Moorman holds that the industry has already solved its off-label Medicaid fraud problem. He says the 1997 authorization of Thomson's Drugdex compendium, which lists many more off-label indications than the other two books Medicaid programs refer to, effectively "legalizes, in some Byzantine way, off-label use so these kinds of cases really can't be brought anymore."	

Minsk agrees with Moorman's conclusion but for a different reason. "Drug companies in the last year or so are trying—at least in their legal departments and senior management—to maybe not be as aggressive as they were a few years ago." However, he says, "You'll probably continue to see subpoenas for drug companies based on past activities. One, because there's money to be made. Two, because whistleblowers are reading these things in the paper. Three, because drug companies are not particularly popular right now, and somebody's got to take the fall. The pendulum is shifting toward enforcement against the drug industry for past activities. That will probably persist for several more months, if not for another year or so."	

, few, or none? The consensus among those that 

 attorneys alike, is that there will be others but few, if any, based on contemporary activity. Why then is US Attorney Sheehan, who is in a position to know, traversing the nation calling 

 a "watershed"? Perhaps it's his way of firing a warning shot across the industry's bow.	

 is one of a kind, it is almost certainly not the last 

 action pharma will ever see for these reasons:	

The increased federalization of healthcare, most notably the new Medicare drug benefit, will increase the scope of FCA. 	

Inventing new prosecutorial theories for the pharmaceutical industry "is not that difficult," the consultant says, because "pharmaceutical manufacturers have many different relationships with physicians and providers and are involved in many different aspects and forms of education and promotion, condoned by law." Its very complexity makes it "fertile ground" for new notions of wrongdoing.	

Although "the aggressiveness with which healthcare fraud has been pursued has waxed and waned over the decades," according to Hyman, "we are currently at an all-time high in terms of the level of enforcement and the associated 'law and order' rhetoric." Blame the 1996 Health Insurance Portability and Accountability Act (HIPAA). It has spurred, Hyman says, a "drive for accountability that has resulted in an unprecedented number of civil and criminal enforcement actions; the transfer of billions of dollars from providers and insurers to the federal government and whistleblowers; the expenditure of tens of millions of dollars on lawyers, accountants, consultants, and compliance programs; and vehement protests by providers." Fraud control, it turns out, "is like most other goods and services: the more one is prepared to spend, the more one can purchase."	

What's at stake? Obviously, pharma's pocketbook. To paraphrase Senator Dirksen, a couple of hundred million dollars here and there, and pretty soon you're talking real money. But neither the solvency nor survival of the industry is at risk, not in the short run anyway. Its reputation is, however—which may, in the long term, amount to the same thing. If public trust declines, increased regulation and enforcement are likely.	

What can pharma do? The big picture requirement—beyond the necessary off-label audits, training, and supervision, beyond FDA "safe harbors" and the PhRMA code—may be an attitude adjustment.	

It's worth heeding Moorman: "Businessmen have a tendency to be contemptuous of regulation. My father was in the securities business and he hated the Securities and Exchange Commission. The drug industry views FDA as a nuisance. It could be a little more statesmanlike and recognize that the FDA is what stands between them and crime."	

Yes, the recent surge in healthcare fraud enforcement has its share of aggressive and selective prosecution."It is relatively easy," as Hyman says, "to condemn billing by sham entities, billing for services not provided, or billing for 12.5 miles of one-inch adhesive tape for a single patient (sufficient to wrap the patient head-to-toe six times a day for six months). But it is quite another matter when the issue involves novel services, delivery arrangements, 'creative billing,' the consequences of the exercise of clinical discretion, compliance with relational contracts, and other 'gray areas' in the law."	

But many instances of off-label promotion have been similarly aggressive. "Drug manufacturers have acted as though Medicare/Medicaid was free money they could grab any way they wanted," says Moorman. "If you read the complaint in the Neurontin case, it's clear that Warner-Lambert was so contemptuous of FDA it turned the preparation of research papers over to its marketing department. Boy, that is asking for trouble. And when you ask for trouble, sooner or later it comes."	

Pfizer is embroiled in a whistleblower lawsuit based on an unproven legal theory with the potential "to scare the hell out of a lot of drug companies," says attorney Alan Minsk of Arnall Golden Gregory. If upheld, even those compliant with FDA regulations for off-label promotion might still be liable for Medicaid fraud under the federal False Claims Act (FCA).

Is Everyone a Target?

Philippe Cini, PhD, is a managing consultant of Tunnell Consulting, located in King of Prussia, Pennsylvania. He can be reached at cini@tunnellconsulting.com or (610) 715-1888.  Raymond E. Schneider is Tunnell Consulting’s vice-president and practice director of Process/Organizational Excellence. He can be reached at

 schneider@tunnellconsulting.com or (610) 337-0820.

Antiquated manufacturing processes cost pharma money—a fact widely known and accepted in the industry. At some facilities, rejected batches, rework, and lengthy investigations have become a way of life, and by some estimates can inflate production costs by as much as 10 percent. According to G.K. Raju, executive director of the Pharmaceutical Manufacturing Initiative at the Massachusetts Institute of Technology, manufacturing consumes an estimated 25 percent of drug company revenues.  	

That is a far cry from the standard of excellence cited by new FDA commissioner Mark McClellan, who wants pharma to match the semiconductor standard of only 0.0001 percent rejected for unacceptable quality. Why such a discrepancy? The FDA regulations that require approval of nearly every change to manufacturing processes give companies little incentive to modernize. 	

But FDA wants to change that. In August 2002, it launched the Process Analytical Technology (PAT) initiative, which it says is a "a framework for allowing regulatory processes to more readily adopt state-of-the-art technological advances in drug development, production and quality assurance." More important, the agency is promoting a transformative vision of pharma manufacturing: every batch of product manufactured right the first time and automatically released as soon as it reaches the end of the production line.   	

Although achieving that vision would produce quantum benefits in cost, compliance, and safety, uncertainty about the real meaning of the initiative has hindered its acceptance. Many in the industry saw PAT as a purely technological effort. But the agency wasn't just encouraging the use of near infrared spectroscopy and other in-process measuring tools. So in August 2003, it issued a new guidance that clears up much of the uncertainty and makes it clear that its initiative covers far more than technology. "It is important to note that the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner," says the August 2003 document. It also outlines the set of tools involved, which are grouped into four broad categories.  (See "More Than Technology," page 92.)	

Yet transformation won't come easy. Formidable obstacles remain, including the industry's ingrained aversion to risk (which was exacerbated by the former regulatory environment), a scientific culture that sometimes resists change, and a failure to import best practices from other process industries, most often because of academic and professional silos as well as regulatory barriers.	

This article outlines the benefits of modernizing manufacturing, addresses the reasons companies are reluctant to embrace the initiative, explains the various technologies covered by the initiative, and shows how companies can adopt a step-by-step approach to manufacturing innovation that can be applied to both new drugs and the processes used with existing drugs.		

The benefits of improved manufacturing are well known: higher quality, higher compliance, improved operator safety, fewer lost batches, fewer deviations, shorter cycle times, and more data-driven decision making. Yet overall industry performance remains poor. For example, Raju has shown that quality-control (QC) testing times are at least as long as processing times and significantly greater in several instances. (See "Time Well Spent?")	

With manufacturing costing 25 percent of revenues, even a 1 percent improvement in efficiency produces significant financial benefits. For a company with $20 billion in annual revenue, every 1 percent reduction in manufacturing cost translates into savings of $50 million a year (.25 x $20 billion = $5 billion x .01 = $50 million).	

Pharma companies often overlook two other significant benefits of using advanced production technology. First, the developing and filing of manufacturing processes that use proprietary or analytical technology can provide a significant barrier to entry for generic competitors. Second, the ability to provide evidence that a drug was consistently manufactured to exacting standards may prove persuasive if its quality or consistency is questioned in court. That is especially important today, when plaintiffs' lawyers, flush with cash from tobacco and asbestos litigation, are taking aim at drug makers. 	

Despite the benefits of PAT, conversations with pharma executives reveal some common, but misguided, reasons for rejecting it. Some of the most frequently heard rationalizations—and their counter-arguments—are as follows: 	

. Many executives believe submitting process applications that involve PAT techniques may slow down the regulatory review and approval process. 		

Keenly aware of that concern, FDA is training and certifying a team of reviewers, compliance officers, and investigators on PAT issues and new technology to manage the review and inspection process. With a thorough understanding of policy goals and innovative technology, those teams should be able to respond to companies' initiatives quickly and comprehensively. "Our new strategy is intended to alleviate the fear among manufacturers that introducing new manufacturing technologies will result in regulatory impasse," says the 2003 guidance.	

FDA also urges pharma companies to communicate their PAT plans early and to consider the agency a partner in moving PAT forward. A subcommittee composed of senior pharma and generic manufacturers, government officials, and private and academic consultants provided their recommendations for the PAT guidance. The document itself urges the creation of "communication mechanisms" such as meetings between the agency and industry, and informal communications between FDA and manufacturers during drug development. In addition, the guidance suggests that when manufacturers consult with the agency, they may want to discuss not only specific PAT plans but also thoughts on a possible regulatory path. 	

 Executives' second-biggest concern is that applying analytical technology to existing processes may reveal situations better left alone. Some companies fear that the application of better manufacturing techniques will uncover problems with current processes that must be reported to FDA, resulting in costly and time-consuming remediation. 		

Problems are likely to surface eventually anyway, but with a PAT program in place, manufacturers are more likely to detect problems in their early stages rather than at the final release of the product or after the problem has become a full-blown regulatory crisis. Early detection allows early correction, often while the product is still within specifications. And it is far better for a company to develop a corrective plan on its own terms rather than under the pressure, direction, and deadlines of regulatory authorities. If a serious problem does emerge, it must, of course, be reported—PAT does not confer a waiver of such regulations—but even a serious problem is better caught early, before it becomes a disaster.	

 Ever conscious of the bottom line, companies also fear that applying on-line (in-process) technology could be prohibitively expensive.	

Costs will skyrocket only if the technology is indiscriminately applied to every process parameter. But by selectively applying technology to the few key parameters that affect variation, companies can not only keep costs down but also significantly increase their return on investment.	

Generally, on-line technology, which provides nearly instantaneous and continuous measurement, should be applied as close to the front end of the manufacturing process as possible, which allows companies to monitor and control the true source of process variation and get the most out of their PAT investment.	

 As FDA points out, "real-time or near real-time measurement tools typically generate large volumes of data," and production managers fear that analytical technology will generate more data than can be managed and used.	

Just as reducing technology costs requires managers to identify key process parameters, managing the information generated requires them to precisely target what information is useful, how it can best be shared, and with whom. 	

 There seems to be some misunderstanding about which processes FDA had in mind; the original PAT initiative appeared to emphasize the use of innovative manufacturing during drug development.	

But FDA's 2003 guidance explicitly says, "We encourage the use of PAT strategies for the manufacture of currently approved products." FDA also recognizes that processes created during small-scale drug development cannot simply be transferred to commercial production. Scale-up is far from an exact science. The processes based on the limited data available during drug development may be improved in light of the mountains of new data that emerge from commercial-scale manufacturing. 	

Considering the enormous potential benefits, pharma companies should view PAT as a long-term strategic initiative rather than as a series of short-term projects. The framework for such a comprehensive initiative includes five interdependent elements:  			

identify critical parameters  to reduce variation

implement an integrated data management infrastructure

implement organizational changes to ensure sustainability (See "Five-Step Program," page 94)

 Company leaders should begin with a vision. By developing a vivid description of the end state desired, they can establish the basis for strategy development. For example, many pharma companies focus their vision on quality. They want every batch in every plant to be done right the first time: No rejections, no rework, no deviations. But that represents only one of many alternative visions—each company must develop the overall view that is right for its circumstances. 

A clear vision enables leaders to identify the critical areas on which it needs to focus: 	

Although a company may ultimately choose to concentrate on a few areas only, by considering all of them in the context of its vision, it will avoid the pitfalls of isolated and uncoordinated elements that do not add up to a strategy. 

Despite FDA's assertion that companies should be bold—that they need only communicate fully with the agency, which is prepared to accommodate new strategies and new technology—many fear that genuine innovations will take longer to win approval. To allay that fear, companies should also make mitigating the risk of pursuing PAT an integral part of their strategy. 	

 Improving manufacturing requires companies to identify what causes variation in critical release parameters (the specifications that must be filed with FDA) and to reduce those variations. That doesn't mean companies should apply on-line technology to all measurements that would otherwise be made off-line—which is unnecessary and prohibitively expensive. PAT technology should be applied to the upstream parameters that are responsible for the variation in the finished product, enabling corrective action before out-of-specification problems occur.	

Statistical tools such as process capability indexes including Cpk—which provides a quantitative assessment of how capable a process parameter is of meeting its specification limits—control charts, regression analysis, and design of experiments can establish the causal relationships between a finished product release parameter and other in-process parameters and raw-material specifications. In existing manufacturing processes, control charts help identify process data patterns that indicate a potential problem. When using control charts, shifts, trends, or outliers (statistical anomalies) can be correlated with a change in the process or a raw material, providing insight into the root cause of the problem.			

For processes under development, the challenge is somewhat different. New processes yield limited amounts of data. Another powerful tool can help: the design of experiment. This statistical technique enables quantitative testing of the effects of several parameters at once, reducing the number of experiments required. As with regression analysis, it generates a table of effects that identifies the key drivers of variations and thus the prime candidates for PAT applications.	

Antiquated manufacturing processes cost pharma money-a fact widely known and accepted in the industry. At some facilities, rejected batches, rework, and lengthy investigations have become a way of life, and by some estimates can inflate production costs by as much as 10 percent. According to G.K. Raju, executive director of the Pharmaceutical Manufacturing Initiative at the Massachusetts Institute of Technology, manufacturing consumes an estimated 25 percent of drug company revenues.

Pharmaceutical Executive-03-01-2004

DTC: European Style

The Ins and Outs of EAPs

Is Everyone a Target?

Table of Contents

The Push for Modern Manufacturing